1. Field of the Invention
This invention relates to an agent for treating disorders from cerebral neuro-degeneration comprising a specified cyclopropachromen derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
2. Prior Art
Organic and functional disorders in the human brain which controls high grade mental actions and motor functions are critical diseases that concern not only the physical but also the mental well-being of a person. In a rapidly aging society, the development of effective methods of treating brain disorders as well as therapeutic drugs is of pressing importance. However, despite many years of studies conducted to unravel the functions of the brain, only a partial understanding has so far been achieved and an understanding of individual diseases, still less a comprehensive and systematic knowledge of the brain, has not yet been obtained.
While many brain diseases are known today, Alzheimer's disease (hereinafter sometimes abbreviated as AD) and senile dementia of the Alzheimer's type (hereinafter sometimes referred to as SDAT), both of which are progressive organic diseases of the brain that are characterized by lowered cognitive capabilities due to the degenerative atrophy of neurocytes in the brain, are becoming major social concerns requiring the implementation of effective care methods since the number of patients suffering from these diseases, especially in industrialized countries is rapidly increasing, and the progression of these diseases results in severe disability and ultimate death for those afflicted.
Under these circumstances, industrialized countries are engaged in nationwide projects for the establishment of effective methods for treating AD and SDAT. However, even the causes of the diseases have not been properly elucidated. Only the morphological changes that can be observed in the brain or the biochemical changes as the consequences have been partly unravelled, but no effective therapy has yet been established.
Cholinergic agents including choline precursors, cholinesterase inhibitors, etc. are being tested, on the basis of the cholinergic theory, in clinical fields as nosotropic agents for treating AD and SDAT. However, the evaluation on the utility of these therapeutics is varied and no single drug exhibits definite therapeutic effects.
Three basic methods may be conceived of to treat neurodegenetative diseases including AD and SDAT: (1) suppressing or preventing the degerative process of neurons; (2) compensating for the lost function of neurons with a drug; and (3) promoting the plasticity of remaining neurons to form a new neuro-circuit. The aforementioned cholinergic agents and cholinesterase inhibitors are within the class (2) since they are focused on the fact that, in a characteristic pathological symptom of AD and SDAT, cholinergic nerve fascicles that project from the basal forebrain to the cerebral cortex and the hippocampus undergo atrophic degeneration, yet acetylcholine receptors in the cerebral cortex and the hippocampus which are the cells that control those cholinergic nerve fascicles remain in a normal state. These drugs are expected to work effectively in the case of dysfunction of acetylcholine systems but no definite therapeutic effects are anticipated for diseases such as AD and SDAT which cannot be fully explained solely on the basis of the dysfunction of acetylcholine systems.
Aggravation of brain diseases could be prevented if the degenerative process of neurons could be suppressed as in (1). If a new neuron network could be formed by promoting the compensatory functional recovery of remaining neurons as in (3), not only could the progress of the diseases be prevented but also positive recovery of neurofunctions could reasonably be expected.
A drug that has been proposed in line with these approaches is a nerve growth factor (which is hereinafter referred to as "NGF"). NGF has long been known as a factor that is essential to the existence of sympathetic ganglion and sensory ganglion neurons in the peripheral nervous system, and hence extensive studies have been conducted on NGF. Recently, it has become clear that NGF also takes part in the existence and sustained functions of cholinergic neurons in the basal forebrain which are important to memory and learning. Thus the possibility of using NGF as an effective means of recovering part of the brain functions has been studied. However, NGF is a basic protein having a molecular weight of ca. 27,000 and the efforts to develop a direct method of compensatory therapy using NGF have not yet achieved a prospect for applicaton in clinical fields since they involve many problems to be solved as regards the methods of its production and administration.
Under these circumstances, increasing attention has recently been drawn by ganglioside as a non-peptide trophic factor like substance. For example, L. Facci et al. reported in J. Neurochem., 42, 299-305 (1985) that monosialoganglioside (GM.sub.1) promoted the formation of nerve dendrites in cultured cells derived from mouse neuroblasts. L. F. Agnati et al., Acta Physiol. Scand., 119, 347-364 (1983) and G. Toffano et al., Brain Res., 296, 233-239 (1984) reported that GM.sub.1 inhibited the degeneration of the cell body of nigra dopamine neurons that occurred after the removal of the cortex on one side of the brain. Further, G. Jonsson et al. reported in Neurosci. Lett. (Suppl.), 14, 185 (1983) that GM.sub.1 worked suppressively on the decrease in 5-HT in the frontal and occipital lobes that was caused by pretreatment with 5,7-dihydroxytriptamine. These reports did not make it clear whether the action of ganglioside was direct or indirect in relation to the intermediary of the neurotrophic factor in NGF but they did show that ganglioside had the ability to either inhibit the degeneration of neurons or promote the compensatory functional recovery of a degenerated nerve circuit. Therefore, these observations suggest the possibility of new pharmaceutical therapy of AD and SDAT.
In fact, however, ganglioside is a glycosphingolipid containing sialic acid and GM.sub.1, too, is a high-molecular weight compound that is the condensate of sialic acid, four saccharides and ceramide. Hence, the use of ganglioside as a drug for treating AD and SDAT involves several problems to be solved in terms of the methods of preparation and administration.